Pharmaceutical Propylene Glycol Solvate Compositions

ABSTRACT

The invention relates to pharmaceutical compositions comprising propylene glycol solvates of APIs.

CROSS REFERENCE TO RELATED APPLICATIONS AND INCORPORATION BY REFERENCE

This application is a divisional of U.S. Ser. No. 10/747,742, filed Dec.29, 2003, now allowed, which claims the benefit of U.S. ProvisionalApplication No. 60/486,713, filed Jul. 11, 2003, U.S. ProvisionalApplication No. 60/459,501, filed Apr. 1, 2003, U.S. ProvisionalApplication No. 60/456,608, filed Mar. 21, 2003, U.S. ProvisionalApplication No. 60/456,027, filed Mar. 18, 2003, U.S. ProvisionalApplication No. 60/441,335, filed Jan. 21, 2003, and U.S. ProvisionalApplication No. 60/437,516, filed Dec. 30, 2002. The content of each ofthese applications is hereby incorporated by reference in its entirety.

FIELD OF THE INVENTION

The present invention relates to drug-containing compositions,pharmaceutical compositions comprising such drugs, and methods forpreparing same.

BACKGROUND OF THE INVENTION

Drugs in pharmaceutical compositions can be prepared in a variety ofdifferent forms. Such drugs can be prepared so as to have a variety ofdifferent chemical forms including chemical derivatives or salts. Suchdrugs can also be prepared to have different physical forms. Forexample, the drugs may be amorphous or may have different crystallinepolymorphs, perhaps existing in different solvation or hydration states.By varying the form of a drug, it is possible to vary the physicalproperties thereof. For example, crystalline polymorphs typically havedifferent solubilities from one another, such that a morethermodynamically stable polymorph is less soluble than a lessthermodynamically stable polymorph. Pharmaceutical polymorphs can alsodiffer in properties such as shelf-life, bioavailability, morphology,vapor pressure, density, color, and compressibility. Accordingly,variation of the solvation state of a drug is one of many ways in whichto modulate the physical properties thereof.

A solvate may be defined as a compound formed by solvation, for exampleas a combination of solvent molecules with molecules or ions of asolute. Well known solvent molecules include water, alcohols and otherpolar organic solvents. Alcohols include methanol, ethanol, n-propanol,isopropanol, n-butanol, isobutanol, and t-butanol. Alcohols also includepolymerized alcohols such as polyalkylene glycols (e.g., polyethyleneglycol, polypropylene glycol). The best-known and preferred solvent istypically water, and solvate compounds formed by solvation with waterare termed hydrates.

Propylene glycol (1,2-propanediol) is a known substance which is aliquid at ambient temperature. As far as the applicants are aware,propylene glycol is not generally well-known for use in the formation ofsolvates. U.S. Pat. No. 3,970,651 does disclose the use of propyleneglycol in the formation of a crystalline cephalosporin derivative.According to this disclosure a propylene glycolate derivative of aspecific cephalosporin zwitterion may be formed in the presence ofpropylene glycol at acidic pH. This disclosure indicates that thepropylene glycol derivative is more stable in solid form than thecorresponding ethanolate, especially having excellent colour stabilityand thermal stability. No other solvates are disclosed in this U.S.patent other than the specific solvate of cephalosporin.

In pharmaceutical formulations certain chemical classes of drugs poseparticular problems in preparing pharmaceutical formulations for medicaluse. One such problem arises in the case of hygroscopic drugs, whichtend to absorb water from the air. This is disadvantageous because itmakes storage of the drug difficult and can cause degradation of thedrug in some cases. Such compounds must be handled in controlledhumidity environments during manufacture in order to prevent potencyerrors due to the changing weight of the drug. The final product must bepackaged in individual moisture resistant blisters in order to preventchanges in or degradation of the product. Another problem arises fromvariable hydration states: molecules may change to a more or less stableform as water, a volatile liquid, is lost. Such changes have been knownto cause some hydrates to become amorphous. Likewise, absorption ofwater by a hygroscopic molecule can plasticise the system and lead torecrystallization as a less stable polymorph.

SUMMARY OF THE INVENTION

Solvates are rarely used in pharmaceuticals because the solvents areusually volatile thus making it difficult to maintain the solvent in thecrystal. If one were to desolvate a pharmaceutical solvate or if itdesolvated due to storage conditions or otherwise, it could lead to theformation of multiple polymorphs or complete collapse of the crystalstructure, forming an amorphous compound with different physicalproperties. Obviously, this batch-to-batch variability and questionableshelf life is undesired. Typically people find solvates of commonsolvents, such as propanol and ethanol. Propylene glycol is similar instructure to propanol, but is not thought of as a solvent. Propyleneglycol solvates of the present invention desolvate only at considerablyhigher temperatures and harsher conditions than traditional solvates.Propylene glycol solvates are also pharmaceutically acceptable in muchlarger amounts thanone would expose people to with a traditionalsolvate. Thus, the propylene glycol solvates of the present inventionhave characteristics that are vastly superior to traditional solvates.

It has now been found that amorphous, crystalline, hygroscopic, orpoorly soluble drugs can be made more soluble, more stable, and lesshygroscopic and can be prepared simply, reliably and inexpensively.

In a first aspect, the present invention provides a pharmaceuticalcomposition comprising a propylene glycol solvate of a drug which ishygroscopic or has low aqueous solubility.

It has surprisingly been found that by using propylene glycol to form asolvate of a hygroscopic drug, the hygroscopicity of the drug isdecreased and/or the stability and aqueous solubility is increased. Thedrug is therefore much easier to formulate and store than itscounterpart untreated or hydrated form.

A number of advantages have been found from the use of propylene glycolin this way. First of all, a higher temperature is required to removepropylene glycol as compared with water or ethanol. This thereforeresults in an increased thermal stability. Thus the invention furtherrelates to methods of making a pharmaceutical solvate more stable athigh temperatures by making a PG solvate of the drug. Secondly,propylene glycol solvates are generally more pharmaceutically acceptablethan other common solvates, including those formed from alcohols otherthan ethanol. It has further been found that the PG solvates of thepresent invention have fewer solvation states than hydration states.This is beneficial because production and quality of a drug can be morepredictable and consistent. Thus an aspect of the present inventionrelates to methods of reducing the number of hydration states by makinga PG solvate of a drug. PG solvates are also beneficial in addressingthe problem of polymorphism. Thus an aspect of the present inventionrelates to methods of reducing the rate and extent a drug changes formand methods of reducing the chance of making an unwanted form becausethe PG solvates drive production of a single form. Another aspect of thepresent invention relates to changing the crystal habit of the drugcrystal and preventing a drug crystalline habit from changing to adifferent habit.

The invention relates to making a pharmaceutical that can be made as ahydrate, more soluble or stable by forming a PG solvate of the drug.

The invention further relates to making a pharmaceutical more stable ina humid environment by making a PG solvate of the drug.

The invention further relates to making a crystalline compound from apharmaceutical that does not readily crystallize by making a crystallinePG solvate of the drug.

The invention further relates to increasing the solubility of acrystalline pharmaceutical by making a PG solvate of the drug.

The invention further relates to methods of lowering the amount of drugsolvation during wet granulation by making a PG solvate of the drug.

A particularly important aspect of the present invention is therealization that formation of propylene glycol solvates is applicable ina general way to drugs whereby the above advantages may be conferred.For example, the invention further relates to reducing the level ofhygroscopicity of a pharmaceutical metal salt (crystalline, amorphous,solvate (e.g., hydrate)) by forming a PG solvate of the salt.Surprisingly, it has been found that the invention is particularlyapplicable to those drugs that are in the form of metal salts, such asalkali metal or alkaline earth metal salts. This is especially the casewhere the metal is selected from sodium, potassium, lithium, calcium andmagnesium. Such salts can be hygroscopic and it has hitherto beendifficult to find a suitable general means of formulation for thesedrugs.

Generally, the molar ratio of propylene glycol to drug in the solvate isin the range 0.5 to 2, (e.g., 0.5, 1.0, 1.5, 2.0). Depending on thenature of the drug, the ratio of propylene glycol to drug in the solvatemay be approximately 0.25, 0.33, 0.5, 0.67, 0.75, 1.0, 1.5, 2.0 or 3.0.

The composition may further comprise a pharmaceutically-acceptablediluent, excipient or carrier and details of pharmaceutical compositionsare also set out in further detail below. The solvate of thepharmaceutical composition according to the present invention ispreferably in a crystalline form.

Advantageously, the powder X-ray (PXRD) diffraction spectrum of thecomposition according to the invention differs from the correspondingpowder X-ray diffraction spectrum of unsolvated drug by at least oneproperty selected from:

(i) a loss of at least one peak;

(ii) shifting of more than half the peaks at the 2-theta angle by atleast 0.2, 0.3, 0.4, or 0.5 degrees; or

(iii) formation of at least one new peak.

It is preferred that the solvate is stable to temperatures of up to 50degrees C. under a stream of nitrogen gas in a thermogravimetricanalysis apparatus.

The PXRD could be the same if their were a host-guest relationship andthe PG was not completely frozen out. This would be an inclusioncompound rather than a true solvate, but it may still be lesshygroscopic than a hydrate, less prone to solvent loss than an inclusionwith ethanol, less prone to being filled by some toxic co-solvent if PGfits well, and less prone to polymorphism to a less soluble form due toinstability caused by a vacated void in the structure. The DSCtransitions are likely to occur at different temperatures and havedifferent intensities than for the parent molecule and it's otherhydrates/solvates.

In one aspect of the invention, the drug is a hygroscopic drug,including hygroscopic metal salts. A non-exhaustive list of hygroscopicdrugs is set out in Table 1, along with their suppliers and routes ofadministration.

TABLE 1 Hygroscopic Drugs Route(s) of Product (company) Activeingredient Hygroscopic Administration Solu-Medrol (P&U) Methylprednisolone X Intravenous succinate ester Primaxin IV and IM (Merck)Imipenem/cilastatin X (cilastatin) Intravenous/ Intramuscular VitraveneInjection (CIBA) Fomivirsen sodium X Intravenous Baycol (Bayer)Cerivastatin sodium X Oral Synercid IV (Aventis)Dalfopristin/Quinopristin X Intravenous Factrel (Wyeth) Gonadorelin HClX Intravenous/ (decapeptide) Subcutaneous Clindets Pledgets (Stiefel)Clindamycin phosphate X Topical (ester prodrug) Famvir (SKB) FamciclovirX Oral Nascobal Gel (Schwarz) Cyanocobalamin X Intranasal Tasmar (Roche)Tolcapone X Oral Ellence Injection (P&U) Epirubicin HCl X IntravenousColestid (P&U) Colestipol HCl (anion X Oral excluded) PfizerpenInjection (Pfizer) Penicillin G potassium X Intravenous BacitracinInjection Bacitracin (peptide) X Intravenous (Paddock) Lescol (Novartis)Fluvastatin sodium X Oral Voltaren XR (Novartis) Diclofenac sodium XOral Salagen (MGI) Pilocarpine HCl X Oral Urecholine injectionBethanechol chloride X Intravenous (Merck) Syprine (Merck) Trientine2(HCl) X Oral Singulair chewable (Merck) Montelukast sodium X OralMustargen injection Mechlorethamine HCl X Intravenous (Merck)Hydrocortone phosphate Hydrocortisone X Intravenous injection (Merck)phosphate ester Decadron phosphate Dexamethasone X Intravenous injection(Merck) phosphate ester Gastrocrom (Medeva) Chromolyn sodium X OralMestinon (ICN) Pyridostigmine X Oral bromide Adipex-P (Gate) PhentermineHCl X Oral Micardis (Boehringer- Telmisartan X Oral Ingelh.) Cerubidineinjection Daunorubicin HCl X Intravenous (Bedford) Biltricide (Bayer)Praziquantel X Oral Elmiron (Alza) Pentosan polysulfate X Oral sodium

In one embodiment, the formulation comprises celecoxib. Although theinvention is not limited to this particular drug, celecoxib provides asuitable example of the efficacy of the invention. Further details ofcelecoxib are set out below. In a further embodiment, the drug comprisesnaproxen, further details of which are also set out below.

In another aspect of the invention, the drug has low aqueous solubility.Typically, low aqueous solubility in the present application refers to acompound having a solubility in water which is less than or equal to 10mg/ml, when measured at 37 degrees C., and preferably less than or equalto 5 mg/ml or 1 mg/ml. “Low aqueous solubility” can further be definedas less than or equal to 900, 800, 700, 600, 500, 400, 300, 200 150 100,90, 80, 70, 60, 50, 40, 30, 20 micrograms/ml, or further 10, 5 or 1micrograms/ml, or further 900, 800, 700, 600, 500, 400, 300, 200 150,100 90, 80, 70, 60, 50, 40, 30, 20, or 10 ng/ml, or less than 10 ng/mlwhen measured at 37 degrees C. Aqueous solubility can also be specifiedas less than 500, 400, 300, 200, 150, 100, 75, 50 or 25 mg/ml. Asembodiments of the present invention, solubility can be increased 2, 3,4, 5, 7, 10, 15, 20, 25, 50, 75, 100, 200, 300, 500, 750, 1000, 5000, or10,000 times by making a PG solvate of the neutral (crystalline oramorphous), salt, or solvate form (e.g., hydrate, ethanolate,methanolate, isopropanolate, etc.). Further aqueous solubility can bemeasured in simulated gastric fluid (SGF) rather than water. SGF(non-diluted) of the present invention is made by combining 1 g/L TritonX-100 and 2 g/L NaCl in water and adjusting the pH with 200 mM HCl toobtain a solution with a final pH=1.7.

PG solvates of steroids are also included as embodiments of the presentinvention. Steroids are an important class of drugs which have lowaqueous solubility. Particularly important steroids includeacetoxypregnenolone, alclometasone dipropionate, aldosterone,anagestone, norethynodrel, androsterone, betamethasone, budesonide,chlormadinone, chloroprednisone, corticosterone, cortisone,cyclosporine, desogestrel, desoximethasone, desoxycorticosterone,dexamethasone, dichlorisone, dimethisterone, equilenin, equilin,estradiol, estriol, estrogens, estrone, ethisterone, ethynodiol di,ethynyl estradiol, fludrocortisone, fludrocortisone, flunsolide,fluocinolone acetonide, fluorohydrocortisone, fluorometholone,fluoxymesterone, fluprednisolone, flurandrenolide, flurandrenolone,flurogestone, fluticasone propionate, hydrocortisone, hydroxydion,hydroxymethylprogesterone, hydroxyprogesterone, leuprolide,levonorgestrel, loteprednol etabonate, medroxyprogesterone,melengestrol, mesalamine, mestranol, methandrostenolone, methazolamide,methyl testosterone, methylandrostenediol, methylprednisolone,mometasone furoate, norelgestromin, norethandrolone, norethindrone,norethindrone, norethisterone, norgestimate, norgestrel,normethisterone, ondansetron hydrochloride, oxandrolone, oxymetholone,paramethasone, paramethasone, prednisolone, prednisolone, prednisone,pregnenolone, progesterone, prometholone, spironolactone, testosterone,testosterone enanthate, triamcinolone, triamcinolone acetonide,triamcinolone acetonide, vetamethasone disodium phosphate (for somesteroids alternative names are included). Formulating steroid drugspresents a problem because of their low aqueous solubility. Embodimentsof the present invention are methods of increasing the solubility ofsteroids by making a PG solvate. Solubility can be specified asdiscussed above. It is difficult to make crystals of steroids because oftheir planar structure. Crystallization can be facilitated by making PGsolvates. Thus, crystalline PG solvates of steroids and methods ofmaking the same are included in embodiments of the present invention.Steroids generally tend to form non-stoichiometric channel hydrates inwhich water molecules are trapped in channels between planar steroidregions. Thus, embodiments of the present invention include inhibitingchannel formation in steroids by making a PG solvate. Metal salts ofsteroid drugs can be made and are another example of hygroscopic drugs.Thus, steroid PG solvates are in accordance with one aspect of thepresent invention. Steroid drugs, whether hygroscopic or not,surprisingly and advantageously form stoichiometric solvates withpropylene glycol. Further, the dissolution rate and solubility can beincreased with propylene glycol solvates. Thus, the steroid solvateshave surprisingly new properties that make them more favourable forpharmaceutical use and are easier to handle than other forms such ashydrates.

In a further aspect, the present invention provides a method forpreparing a propylene glycol solvate of a drug, which method comprises:

(a) contacting propylene glycol with a drug in solution;(b) crystallizing a propylene glycol solvate of the drug from thesolution; and(c) isolating the solvate. (the drug may be, for example, a hygroscopicdrug or a drug of low aqueous solubility).

In a further aspect, the present invention provides a method fordecreasing the hygroscopicity of a drug, which method comprises:

(a) contacting the drug with propylene glycol in solution;(b) crystallizing a propylene glycol solvate of the drug from thesolution; and(c) isolating the solvate, wherein the solvate has decreasedhygroscopicity as compared to the drug.

In a further aspect, the present invention provides a method forincreasing the aqueous solubility of a drug, which method comprises:

(a) contacting the drug with propylene glycol in solution;(b) crystallizing a propylene glycol solvate of the drug from thesolution; and(c) isolating the solvate, wherein the solvate has increased aqueoussolubility as compared to the drug.

Typically, conditions for making a solvate are the same as for preparingthe corresponding non-solvated form of the drug: the solvate of neutralcompound would not be pH controlled; the solvate of an acid additionsalt would be prepared by including PG with the drug and the acid; andthe solvate of a base addition salt would involve adding the drug, thedesired base, and the PG. Different co-solvent systems, anti-solvents,or temperature conditions may be used to encourage PG solvate formation.Seed crystals may be added if they have previously been prepared andisolated.

The step of isolating the solvate may include separating the solutionphase from the solvate. Any common method of separation may be employed,including filtration and decanting. The crystalline solvate may berinsed one or more times with an appropriate solvent followingfiltration or decanting. The crystalline solvate is preferably dried toremove excess solution phase. Drying may be carried out by thermalprocessing, vacuum, blowing a stream of gas such as air, nitrogen, argonor another inert gas, or a combination of any or all of these methods.The intention of the rinsing and drying steps is to remove impuritiesincluding residual co-solvents and excess PG, acid, or base if used.

The invention will now be described in further detail, by way of exampleonly, with reference to the accompanying drawings.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows a thermogravimetric analysis of a propylene glycol solvateof a celecoxib sodium salt.

FIG. 2A-D shows the PXRD pattern of a propylene glycol solvate of acelecoxib sodium salt.

FIG. 3 shows a thermogravimetric analysis of a propylene glycol solvateof a celecoxib potassium salt.

FIG. 4 shows the PXRD pattern of a propylene glycol solvate of acelecoxib potassium salt.

FIG. 5 shows a thermogravimetric analysis of a propylene glycol solvateof a celecoxib lithium salt.

FIG. 6 shows the PXRD pattern of a propylene glycol solvate of acelecoxib lithium salt.

FIG. 7 shows the thermogravimetric analysis of a propylene glycolsolvate of naproxen sodium salt.

FIG. 8 shows a PXRD pattern of a propylene glycol solvate of naproxensodium salt.

FIG. 9 shows the thermogravimetric analysis of a propylene glycolsolvate of olanzapine form I.

FIG. 10 shows the differential scanning calorimetry thermogram of apropylene glycol solvate of olanzapine form I.

FIG. 11A-B shows PXRD patterns of a propylene glycol solvate ofolanzapine form I.

FIG. 12 shows a packing diagram of olanzapine form I PG solvate.

FIG. 13 shows the thermogravimetric analysis of a propylene glycolsolvate of cortisone acetate.

FIG. 14 shows the differential scanning calorimetry thermogram of apropylene glycol solvate of cortisone acetate.

FIG. 15A-B shows PXRD patterns of a propylene glycol solvate ofcortisone acetate.

FIG. 16 shows a PXRD pattern of cortisone acetate.

FIG. 17 shows a packing diagram of cortisone acetate PG solvate.

FIG. 18 shows the thermogravimetric analysis of a trihydrate ofcelecoxib sodium PG solvate.

FIG. 19 shows the PXRD pattern of a trihydrate of celecoxib sodium PGsolvate.

FIG. 20 shows the thermogravimetric analysis of a trihydrate ofcelecoxib sodium PG solvate.

FIG. 21 shows the PXRD pattern of a trihydrate of celecoxib sodium PGsolvate.

FIG. 22 shows the PXRD pattern of celecoxib sodium salt.

FIG. 23 shows the PXRD pattern of celecoxib lithium salt.

FIG. 24 shows the PXRD pattern of celecoxib potassium salt.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to propylene glycol solvate forms,preferably stoichiometric, of certain drugs, including those which arehygroscopic or have low aqueous solubility. Whilst the invention isapplicable to any such drugs in general, metal salts of thenon-steroidal anti-inflammatory drug celecoxib serve to illustrate thepresent invention by way of example. Unlike traditional non-steroidalanti-inflammatory drugs (NSAIDs), celecoxib is a selective inhibitor ofcyclooxygenase II (COX-2) which causes fewer side effects whenadministered to a subject. The present applicants have identified newforms of celecoxib that have improved properties, particularly as oralformulations. The applicants have found that a stable, crystallinesodium salt of celecoxib can be synthesised which is significantly moresoluble in water than the neutral celecoxib on the market. This sodiumsalt, or other metal salts can subsequently be improved according to thepresent invention by the production of a propylene glycol solvatethereof.

Salts of celecoxib are formed by reaction of celecoxib with anacceptable base. Acceptable bases include, but are not limited to, metalhydroxides and alkoxides with sufficiently high pK_(a)'s (e.g., pK_(a)'sgreater than about 11 to about 12).

Naproxen is a further API which may be used to illustrate the presentinvention. Naproxen is a member of the ibufenac group of NSAIDs. ThisAPI is practically insoluble in water. Other examples of illustrationsof the present invention include olanzapine and cortisone acetate.

An aspect of the present invention provides a pharmaceutical compositioncomprising a propylene glycol solvate of a drug that is less hygroscopicthan the amorphorous, neutral crystalline, or salt crystalline form,and/or has greater aqueous solubility. Hygroscopicity should be assessedby dynamic vapor sorption analysis, in which 5-50 mg of the compound issuspended from a Calm microbalance. The compound being analyzed shouldbe placed in a non-hygroscopic pan and its weight should be measuredrelative to an empty pan composed of identical material and havingnearly identical size, shape, and weight. Ideally, platinum pans shouldbe used. The pans should be suspended in a chamber through which a gas,such as air or nitrogen, having a controlled and known percent relativehumidity (% RH) is flowed until equilibrium criteria are met. Typicalequilibrium criteria include weight changes of less than 0.01% changeover 3 minutes at constant humidity and temperature. The relativehumidity should be measured for samples dried under dry nitrogen toconstant weight (<0.01% change in 3 minutes) at 40 degrees C. unlessdoing so would de-solvate or otherwise convert the material to anamorphous compound. In one aspect, the hygroscopicity of a driedcompound can be assessed by increasing the RH from 5 to 95% inincrements of 5% RH and then decreasing the RH from 95 to 5% in 5%increments to generate a moisture sorption isotherm. The sample weightshould be allowed to equilibrate between each change in % RH. If thecompound deliquesces or becomes amorphous between above 75% RH, butbelow 95% RH, the experiment should be repeated with a fresh sample andthe relative humidity range for the cycling should be narrowed to 5-75%RH or 10-75% RH instead of 5-95%RH. If the sample cannot be dried priorto testing due to lack of form stability, than the sample should bestudied using two complete humidity cycles of either 10-75% RH or 5-95%RH, and the results of the second cycle should be used if there issignificant weight loss at the end of the first cycle.

Hygroscopicity can be defined using various parameters. For purposes ofthe present invention, a non-hygroscopic molecule should not gain orlose more than 1.0%, or more preferably, 0.5% weight at 25 degrees C.when cycled between 10 and 75% RH (relative humidity at 25 degrees C.).The non-hygroscopic molecule more preferably should not gain or losemore than 1.0%, or more preferably, 0.5% weight when cycled between 5and 95% RH at 25 degrees C., or more than 0.25% of its weight between 10and 75% RH. Most preferably, a non-hygroscopic molecule will not gain orlose more than 0.25% of its weight when cycled between 5 and 95% RH.

Alternatively, for purposes of the present invention, hygroscopicity canbe defined using the parameters of Callaghan et al., Equilibriummoisture content of pharmaceutical excipients, in Drug Dev. Ind. Pharm.,Vol. 8, pp. 335-369 (1982). Callaghan et al. classified the degree ofhygroscopicity into four classes.

Class 1: Non-hygroscopic Essentially no moisture increases occur atrelative humidities below 90%.

Class 2: Slightly hygroscopic Essentially no moisture increases occur atrelative humidities below 80%.

Class 3: Moderately hygroscopic Moisture content does not increase morethan 5% after storage for 1 week at relative humidities below 60%.

Class 4: Very hygroscopic Moisture content increase may occur atrelative humidities as low as 40 to 50%.

Alternatively, for purposes of the present invention, hygroscopicity canbe defined using the parameters of the European Pharmacopoeia TechnicalGuide (1999, p. 86) which has defined hygrospocity, based on the staticmethod, after storage at 25 degrees C. for 24 h at 80% RH:

Slightly hygroscopic: Increase in mass is less than 2 percent m/m andequal to or greater than 0.2 percent m/m.

Hygroscopic: Increase in mass is less than 15 percent m/m and equal toor greater than 0.2 percent m/m.

Very hygroscopic: Increase in mass is equal to or greater than 15percent m/m.

Deliquescent: Sufficient water is absorbed to form a liquid.

PG solvates of the present invention can be set forth as being in Class1, Class 2, or Class 3, or as being Slightly hygroscopic, Hygroscopic,or Very hygroscopic. PG solvates of the present invention can also beset forth based on their ability to reduce hygroscopicity. Thus,preferred PG solvates of the present invention are less hygroscopic thanthe non-PG solvated reference compound, e.g., the reference compound ofa celecoxib sodium salt PG solvate is celecoxib sodium salt. Furtherincluded in the present invention are PG solvates that do not gain orlose more than 1.0% weight at 25 degrees C. when cycled between 10 and75% RH, wherein the reference compound gains or loses more than 1.0%weight under the same conditions. Further included in the presentinvention are PG solvates that do not gain or lose more than 0.5% weightat 25 degrees C. when cycled between 10 and 75% RH, wherein thereference compound gains or loses more than 0.5% or more than 1.0%weight under the same conditions. Further included in the presentinvention are PG solvates that do not gain or lose more than 1.0% weightat 25 degrees C. when cycled between 5 and 95% RH, wherein the referencecompound gains or loses more than 1.0% weight under the same conditions.Further included in the present invention are PG solvates that do notgain or lose more than 0.5% weight at 25 degrees C. when cycled between5 and 95% RH, wherein the reference compound gains or loses more than0.5% or more than 1.0% weight under the same conditions. Furtherincluded in the present invention are PG solvates that do not gain orlose more than 0.25% weight at 25 degrees C. when cycled between 5 and95% RH, wherein the reference compound gains or loses more than 0.5% ormore than 1.0% weight under the same conditions.

Further included in the present invention are PG solvates that have ahygroscopicity (according to Callaghan et al.) that is at least oneclass lower than the reference compound or at least two classes lowerthan the reference compound. Non-limiting examples include; a Class 1 PGsolvate of a Class 2 reference compound, a Class 2 PG solvate of a Class3 reference compound, a Class 3 PG solvate of a Class 4 referencecompound, a Class 1 PG solvate of a Class 3 reference compound, a Class1 PG solvate of a Class 4 reference compound, or a Class 2 PG solvate ofa Class 4 reference compound.

Further included in the present invention are PG solvates that have ahygroscopicity (according to the European Pharmacopoeia Technical Guide)that is at least one class lower than the reference compound or at leasttwo classes lower than the reference compound. Non-limiting examplesinclude; a Slightly hygroscopic PG solvate of a Hygroscopic referencecompound, a Hygroscopic PG solvate of a Very Hygroscopic referencecompound, a Very Hygroscopic PG solvate of a Deliquescent referencecompound, a Slightly hygroscopic PG solvate of a Very Hygroscopicreference compound, a Slightly hygroscopic PG solvate of a Deliquescentreference compound, a Hygroscopic PG solvate of a Deliquescent referencecompound.

In another aspect of the present invention, the dissolution profile ofthe API (active pharmaceutical ingredient) (e.g. celecoxib) is modulatedwhereby the aqueous dissolution rate or the dissolution rate insimulated gastric fluid (SGF) or in simulated intestinal fluid (SIF), orin a solvent or plurality of solvents is increased. Dissolution rate isthe rate at which API solids dissolve in a dissolution medium. For APIswhose absorption rates are faster than the dissolution rates (e.g.,steroids), the rate-limiting step in the absorption process is often thedissolution rate. Because of a limited residence time at the absorptionsite, APIs that are not dissolved before they are removed from theintestinal absorption site are considered useless. Therefore, the rateof dissolution has a major impact on the performance of APIs that arepoorly soluble. Because of this factor, the dissolution rate of APIs insolid dosage forms is an important, routine, quality control parameterused in the API manufacturing process.

Dissolution rate=KS(C _(s) −C)  (1)

where K is dissolution rate constant, S is the surface area, C_(s) isthe apparent solubility, and C is the concentration of API in thedissolution media. For rapid API absorption, C_(s)−C is approximatelyequal to C_(s). The dissolution rate of APIs may be measured byconventional means known in the art.

The increase in the dissolution rate of a composition of the presentinvention, as compared to the unsolvated form, may be specified, such asby 10, 20, 30, 40, 50, 60, 70, 80, 90, or 100%, or by 2, 3, 4, 5, 6, 7,8, 9, 10, 15, 20, 25, 30, 40, 50, 75, 100, 125, 150, 175, 200, 250, 300,350, 400, 500, 1000, 10,000, or 100,000 fold greater than the unsolvatedform in the same solution. Conditions under which the dissolution rateis measured are discussed above. The increase in dissolution may befurther specified by the time the composition remains supersaturated.Examples of above embodiments include: compositions with a dissolutionrate, at 37 degrees C. and a pH of 7.0, that is increased at least 5fold over the unsolvated form, compositions with a dissolution rate inSGF that is increased at least 5 fold over the unsolvated form,compositions with a dissolution rate in SIF that is increased at least 5fold over the unsolvated form.

The present invention demonstrates that the length of time in whichcelecoxib or other APIs remains in solution can be increased to asurprising high degree by using a PG solvate form as discussed herein.The presence of propylene glycol allows the formation of asupersaturated solution of the API and a high concentration of API willremain in solution for an extended period of time. Celecoxib, forexample, has a solubility in water of less than 1 microgram/mL andcannot be maintained as a supersaturated solution for any appreciabletime. The present invention has drawn compositions that can bemaintained for a period of time (e.g., 15, 30, 45, 60, minutes andlonger) as supersaturated solutions at concentrations 2, 3, 5, 7, 10,20, 30, 40, 50, 60, 70, 80, 90, or 100%, or by 3, 4, 5, 6, 7, 8, 9, 10,15, 20, 25, 30, 40, 50, 75, 100, 125, 150, 175, 200, 250, 300, 350, 400,500, 1000, 10,000, or 100,000 fold greater than the solubility of theunsolvated form in the same solution (e.g., water or SGF).

The methods of the present invention can be used to make apharmaceutical API formulation with greater solubility, dissolution,bioavailability, AUC, reduced time to T_(max), the average time fromadministration to reach peak blood serum levels, higher C_(max), theaverage maximum blood serum concentration of API followingadministration, and longer T_(1/2), the average terminal half-life ofAPI blood serum concentration following T_(max), when compared to theunsolvated form.

AUC is the area under the plot of plasma concentration of API (notlogarithm of the concentration) against time after API administration.The area is conveniently determined by the “trapezoidal rule”: the datapoints are connected by straight line segments, perpendiculars areerected from the abscissa to each data point, and the sum of the areasof the triangles and trapezoids so constructed is computed. When thelast measured concentration (C_(n), at time t_(n)) is not zero, the AUCfrom t_(n) to infinite time is estimated by C_(n)/k_(el).

The AUC is of particular use in estimating bioavailability of drugs, andin estimating total clearance of drugs (Cl_(T)). Following singleintravenous doses, AUC=D/Cl_(T), where D is the dose, for singlecompartment systems obeying first-order elimination kinetics;alternatively, AUC=C₀/k_(el), where k_(el) is the drug elimination rateconstant. With routes other than the intravenous AUC=F·D/Cl_(T), where Fis the bioavailability of the drug.

Thus, in a further aspect, the present invention provides a process formodulating the bioavailability of an API when administered in its normaland effective dose range, whereby the AUC is increased, the time toT_(max) is reduced, or C_(max) is increased, which process comprises thepreparation of a PG solvate.

Examples of the above embodiments include: compositions with a time toT_(max) that is reduced by at least 10% as compared to the neutral freeform, compositions with a time to T_(max) that is reduced by at least20% over the free form, compositions with a time to T_(max) that isreduced by at least 40% over the free form, compositions with a time toT_(max) that is reduced by at least 50% over the free form, compositionswith a T_(max) that is reduced by at least 60% over the free form,compositions with a T_(max) that is reduced by at least 70% over thefree form, compositions with a T_(max) that is reduced by at least 80%over the free form, compositions with a C_(max) that is increased by atleast 20% over the free form, compositions with a C_(max) that isincreased by at least 30% over the free form, compositions with aC_(max) that is increased by at least 40% over the free form,compositions with a C_(max) that is increased by at least 50% over thefree form, compositions with a C_(max) that is increased by at least 60%over the free form, compositions with a C_(max) that is increased by atleast 70% over the free form, compositions with a C_(max) that isincreased by at least 80% over the free form,

compositions with a C_(max) that is increased by at least 2 times thefree form,compositions with a C_(max) that is increased by at least 3 times thefree form,compositions with a C_(max) that is increased by at least 4 times thefree form,compositions with a C_(max) that is increased by at least 5 times thefree form,compositions with a C_(max) that is increased by at least 6 times thefree form,compositions with a C_(max) that is increased by at least 7 times thefree form,compositions with a C_(max) that is increased by at least 8 times thefree form,compositions with a C_(max) that is increased by at least 9 times thefree form,compositions with a C_(max) that is increased by at least 10 times thefree form,compositions with an AUC that is increased by at least 10% over the freeform, compositions with an AUC that is increased by at least 20% overthe free form, compositions with an AUC that is increased by at least30% over the free form, compositions with an AUC that is increased by atleast 40% over the free form, compositions with an AUC that is increasedby at least 50% over the free form, compositions with an AUC that isincreased by at least 60% over the free form, compositions with an AUCthat is increased by at least 70% over the free form,compositions with an AUC that is increased by at least 80% over the freeform,compositions with an AUC that is increased by at least 1 times the freeform,compositions with an AUC that is increased by at least 2 times the freeform,compositions with an AUC that is increased by at least 3 times the freeform, orcompositions with an AUC that is increased by at least 4 times the freeform.

The uptake of a drug by a subject can also be assessed in terms ofmaximum blood serum concentration and time to reach maximum blood serumconcentration. Pharmaceutical compositions with a more rapid onset totherapeutic effect typically reach a higher maximum blood serumconcentration (C_(max)) a shorter time after oral administration(T_(max)). Preferably, compositions of the present invention have ahigher C_(max) and/or a shorter T_(max) than in the unsolvated form. TheT_(max) for the compositions of the present invention occurs withinabout 60 minutes, 55 minutes, 50 minutes, 45 minutes, 40 minutes, 35minutes, 30 minutes, 25 minutes, 20 minutes, 15 minutes, 10 minutes, orwithin about 5 minutes of administration (e.g., oral administration).Even more preferably, the therapeutic effects of compositions of thepresent invention begin to occur within about 60 minutes, 55 minutes, 50minutes, 45 minutes, 40 minutes, 35 minutes, 30 minutes, within about 25minutes, within about 20 minutes, within about 15 minutes, within about10 minutes, or within about 5 minutes of administration (e.g., oraladministration).

Compositions of the present invention have a bioavailability greaterthan their respective unsolvated forms. In other embodiments, thecompositions of the present invention have a bioavailability of at least50%, 60%, 65%, 70%, 75%, 80%, 85%, 87%, 90%, 91%, 92%, 93%, 94%, 95%,96%, 97%, 98%, or 99%.

In a particular embodiment of the present invention, administration ofcelecoxib PG solvate to a subject may result in effective pain relief.Pain relief can be attained by inter alia reaching an appropriate bloodserum concentration of a suitable analgesic. In the case of theselective COX-2 inhibitor celecoxib, about 250 ng/mL is an appropriateconcentration for the relief of pain of various causes. Any standardpharmacokinetic protocol can be used to determine blood serumconcentration profile in humans following oral administration of acelecoxib formulation, and thereby establish whether that formulationmeets the pharmacokinetic criteria set out herein. The prior artincludes many examples of pharmacokinetic studies and as such U.S. Pat.No. 6,579,895 and WO 01/91750 are hereby included as references in theirentirety.

In a further aspect the present invention provides a process forimproving the dose response of an API by making a composition of thepresent invention. Dose response is the quantitative relationshipbetween the magnitude of response and the dose inducing the response andmay be measured by conventional means known in the art. The curverelating therapeutic effect (as the dependent variable) to dose (as theindependent variable) for an API-cell system is the “dose-responsecurve”. Typically, the dose-response curve is the measured response toan API plotted against the dose of the API (mg/kg) given. The doseresponse curve can also be a curve of AUC against the dose of the APIgiven.

The dose-response curve for many APIs (e.g. presently-marketed celecoxib(CELEBREX™)) is nonlinear. Preferably, the dose-response curves for thePG solvate compositions of the present invention are linear or contain alarger linear region than presently-marketed celecoxib. A preferredembodiment of the present invention may incorporate a dose-responsecurve with a linear slope that is steeper than that of celecoxib. Thiswould allow a faster-onset of therapeutic relief from a smaller dosageof API. An initially steep dose-response curve which gradually levelsout could be employed to generate a controlled-release formulation.Also, the absorption or uptake of many APIs (e.g. presently-marketedcelecoxib) depends in part on food effects, such that uptake of the APIincreases when taken with food, especially fatty food. Preferably,uptake of the PG solvates of the present invention exhibit a decreaseddependence on food, such that the difference in uptake of the PGsolvates when taken with food and when not taken with food is less thanthe difference in uptake of the unsolvated form.

The compositions of the present invention, including the activepharmaceutical ingredient (API) and formulations comprising the API, aresuitably stable for pharmaceutical use. Preferably, the API orformulations thereof of the present invention are stable such that whenstored at 30 degrees C. for 2 years, less than 0.2% of any one degradantis formed. The term degradant refers herein to product(s) of a singletype of chemical reaction. For example, if a hydrolysis event occursthat cleaves a molecule into two products, for the purpose of thepresent invention, it would be considered a single degradant. Morepreferably, when stored at 40 degrees C. for 2 years, less than 0.2% ofany one degradant is formed. Alternatively, when stored at 30 degrees C.for 3 months, less than 0.2% or 0.15%, or 0.1% of any one degradant isformed, or when stored at 40 degrees C. for 3 months, less than 0.2% or0.15%, or 0.1% of any one degradant is formed. Further alternatively,when stored at 60 degrees C. for 4 weeks, less than 0.2% or 0.15%, or0.1% of any one degradant is formed. The relative humidity (RH) may bespecified as ambient (RH), 75% (RH), or as any single integer between 1to 99%.

APIs prepared in the form of propylene glycol solvates have severalimportant advantages over other solvates and their free formcounterparts. In general, solvates are more commonly formed with water,methanol, ethanol, or other alcohols than with propylene glycol. Thesemore common solvates are more easily removed from the crystal matrix byelevated temperatures than propylene glycol. PG solvates have anincreased thermal stability over those of more traditional solvates.Also, PG solvates are generally more pharmaceutically acceptable thanother common solvates, including those formed from alcohols other thanethanol. Investigations of the PG solvates of the present invention haveshown fewer solvation states than hydration states. Reference compoundsfor PG solvates can be unsolvated free acid, unsolvated free base,zwitter ions, hydrates, or other solvates (e.g. methanol, ethanol,etc.). This decrease in form diversity associated with PG solvates canlead to more predictability and more consistent results duringproduction and quality control. Stabilization of a desired solvate orpolymorph can be achieved by causing the less desirable forms (e.g.solvates, polymorphs, hydrates) to be energetically less favorable thanthe desired form. In this way, PG solvates can aid in the production ofpharmaceutical formulations with increased form stability.

The present invention further relates to methods of making apharmaceutical solvate more stable at elevated temperatures (e.g. 30,40, 50 degrees C.) by producing a PG solvate of the drug. The presentinvention further relates to methods of making a more pharmaceuticallyacceptable solvate of many APIs by employing propylene glycol ratherthan more biologically harmful solvents (e.g. methanol). The presentinvention further relates to methods of reducing the number of forms(e.g. hydration states, solvation states, polymorphs, etc.) possible fora pharmaceutical solvate.

Pharmaceutically acceptable PG solvates can be administered bycontrolled- or delayed-release means. Controlled-release pharmaceuticalproducts have a common goal of improving drug therapy over that achievedby their non-controlled release counterparts. Ideally, the use of anoptimally designed controlled-release preparation in medical treatmentis characterized by a minimum of drug substance being employed to cureor control the condition in a minimum amount of time. Advantages ofcontrolled-release formulations include: 1) extended activity of thedrug; 2) reduced dosage frequency; 3) increased patient compliance; 4)usage of less total drug; 5) reduction in local or systemic sideeffects; 6) minimization of drug accumulation; 7) reduction in bloodlevel fluctuations; 8) improvement in efficacy of treatment; 9)reduction of potentiation or loss of drug activity; and 10) improvementin speed of control of diseases or conditions. (Kim, Cherng-ju,Controlled Release Dosage Form Design, Technomic Publishing, Lancaster,Pa.: 2000).

Conventional dosage forms generally provide rapid or immediate drugrelease from the formulation. Depending on the pharmacology andpharmacokinetics of the drug, use of conventional dosage forms can leadto wide fluctuations in the concentrations of the drug in a patient'sblood and other tissues. These fluctuations can impact a number ofparameters, such as dose frequency, onset of action, duration ofefficacy, maintenance of therapeutic blood levels, toxicity, sideeffects, and the like. Advantageously, controlled-release formulationscan be used to control a drug's onset of action, duration of action,plasma levels within the therapeutic window, and peak blood levels. Inparticular, controlled- or extended-release dosage forms or formulationscan be used to ensure that the maximum effectiveness of a drug isachieved while minimizing potential adverse effects and safety concerns,which can occur both from under dosing a drug (i.e., going below theminimum therapeutic levels) as well as exceeding the toxicity level forthe drug.

Most controlled-release formulations are designed to initially releasean amount of drug (active ingredient) that promptly produces the desiredtherapeutic effect, and gradually and continually release other amountsof drug to maintain this level of therapeutic or prophylactic effectover an extended period of time. In order to maintain this constantlevel of drug in the body, the drug must be released from the dosageform at a rate that will replace the amount of drug being metabolizedand excreted from the body. Controlled-release of an active ingredientcan be stimulated by various conditions including, but not limited to,pH, ionic strength, osmotic pressure, temperature, enzymes, water, andother physiological conditions or compounds.

A variety of known controlled- or extended-release dosage forms,formulations, and devices can be adapted for use with the PG solvates ofthe present invention. Examples include, but are not limited to, thosedescribed in U.S. Pat. Nos. 3,845,770; 3,916,899; 3,536,809; 3,598,123;4,008,719; 5,674,533; 5,059,595; 5,591,767; 5,120,548; 5,073,543;5,639,476; 5,354,556; 5,733,566; and 6,365,185 131; each of which isincorporated herein by reference. These dosage forms can be used toprovide slow or controlled-release of one or more active ingredientsusing, for example, hydroxypropylmethyl cellulose, other polymermatrices, gels, permeable membranes, osmotic systems (such as OROS®(Alza Corporation, Mountain View, Calif. USA)), multilayer coatings,microparticles, liposomes, or microspheres or a combination thereof toprovide the desired release profile in varying proportions.Additionally, ion exchange materials can be used to prepare immobilized,adsorbed salt forms and thus effect controlled delivery of the drug.Examples of specific anion exchangers include, but are not limited to,Duolite® A568 and Duolite® AP143 (Rohm & Haas, Spring House, Pa. USA).

One embodiment of the invention encompasses a unit dosage form whichcomprises a pharmaceutically acceptable PG solvate, or a polymorph,solvate, hydrate, dehydrate, co-crystal, anhydrous, or amorphous formthereof, and one or more pharmaceutically acceptable excipients ordiluents, wherein the pharmaceutical composition or dosage form isformulated for controlled-release. Specific dosage forms utilize anosmotic drug delivery system.

A particular and well-known osmotic drug delivery system is referred toas OROS® (Alza Corporation, Mountain View, Calif. USA). This technologycan readily be adapted for the delivery of compounds and compositions ofthe invention. Various aspects of the technology are disclosed in U.S.Pat. Nos. 6,375,978 B1; 6,368,626 B1; 6,342,249 B1; 6,333,050 B2;6,287,295 B1; 6,283,953 B1; 6,270,787 B1; 6,245,357 B1; and 6,132,420;each of which is incorporated herein by reference. Specific adaptationsof OROS® that can be used to administer compounds and compositions ofthe invention include, but are not limited to, the OROS® Push-Pull™,Delayed Push-Pull™, Multi-Layer Push-Pull™, and Push-Stick™ Systems, allof which are well known. See, e.g., http://www.alza.com. AdditionalOROS® systems that can be used for the controlled oral delivery ofcompounds and compositions of the invention include OROS®-CT andL-OROS®. Id.; see also, Delivery Times, vol. II, issue II (AlzaCorporation).

Conventional OROS® oral dosage forms are made by compressing a drugpowder (e.g., celecoxib sodium PG solvate) into a hard tablet, coatingthe tablet with cellulose derivatives to form a semi-permeable membrane,and then drilling an orifice in the coating (e.g., with a laser). (Kim,Cherng-ju, Controlled Release Dosage Form Design, Technomic Publishing,Lancaster, Pa.: 2000). The advantage of such dosage forms is that thedelivery rate of the drug is not influenced by physiological orexperimental conditions. Even a drug with a pH-dependent solubility canbe delivered at a constant rate regardless of the pH of the deliverymedium. But because these advantages are provided by a build-up ofosmotic pressure within the dosage form after administration,conventional OROS® drug delivery systems cannot be used to effectivelydeliver drugs with low water solubility. Because PG solvates andcomplexes of this invention (e.g., celecoxib sodium PG solvate) are farmore soluble in water than unsolvated forms, they are well suited forosmotic-based delivery to patients.

A specific dosage form of the invention comprises: a wall defining acavity, the wall having an exit orifice formed or formable therein andat least a portion of the wall being semipermeable; an expandable layerlocated within the cavity remote from the exit orifice and in fluidcommunication with the semipermeable portion of the wall; a dry orsubstantially dry state drug layer located within the cavity adjacent tothe exit orifice and in direct or indirect contacting relationship withthe expandable layer; and a flow-promoting layer interposed between theinner surface of the wall and at least the external surface of the druglayer located within the cavity, wherein the drug layer comprises a PGsolvate, or a polymorph, solvate, hydrate, dehydrate, co-crystal,anhydrous, or amorphous form thereof. See U.S. Pat. No. 6,368,626, theentirety of which is incorporated herein by reference.

Another specific dosage form of the invention comprises: a wall defininga cavity, the wall having an exit orifice formed or formable therein andat least a portion of the wall being semipermeable; an expandable layerlocated within the cavity remote from the exit orifice and in fluidcommunication with the semipermeable portion of the wall; a drug layerlocated within the cavity adjacent the exit orifice and in direct orindirect contacting relationship with the expandable layer; the druglayer comprising a liquid, active agent formulation absorbed in porousparticles, the porous particles being adapted to resist compactionforces sufficient to form a compacted drug layer without significantexudation of the liquid, active agent formulation, the dosage formoptionally having a placebo layer between the exit orifice and the druglayer, wherein the active agent formulation comprises a PG solvate, or apolymorph, solvate, hydrate, dehydrate, co-crystal, anhydrous, oramorphous form thereof. See U.S. Pat. No. 6,342,249, the entirety ofwhich is incorporated herein by reference.

Excipients employed in pharmaceutical compositions of the presentinvention can be solids, semi-solids, liquids or combinations thereof.Compositions of the invention containing excipients can be prepared byany known technique of pharmacy that comprises admixing an excipientwith a drug or therapeutic agent. A pharmaceutical composition of theinvention contains a desired amount of API per dose unit and, ifintended for oral administration, can be in the form, for example, of atablet, a caplet, a pill, a hard or soft capsule, a lozenge, a cachet, adispensable powder, granules, a suspension, an elixir, a dispersion, aliquid, or any other form reasonably adapted for such administration.Presently preferred are oral dosage forms that are discrete dose unitseach containing a predetermined amount of the drug, such as tablets orcapsules.

Non-limiting examples follow of excipients that can be used to preparepharmaceutical compositions of the invention.

Pharmaceutical compositions of the invention optionally comprise one ormore pharmaceutically acceptable carriers or diluents as excipients.Suitable carriers or diluents illustratively include, but are notlimited to, either individually or in combination, lactose, includinganhydrous lactose and lactose monohydrate; starches, including directlycompressible starch and hydrolyzed starches (e.g., Celutab™ and Emdex™);mannitol; sorbitol; xylitol; dextrose (e.g., Cerelose™ 2000) anddextrose monohydrate; dibasic calcium phosphate dihydrate; sucrose-baseddiluents; confectioner's sugar; monobasic calcium sulfate monohydrate;calcium sulfate dihydrate; granular calcium lactate trihydrate;dextrates; inositol; hydrolyzed cereal solids; amylose; cellulosesincluding microcrystalline cellulose, food grade sources of alpha- andamorphous cellulose (e.g., RexcelJ), powdered cellulose,hydroxypropylcellulose (HPC) and hydroxypropylmethylcellulose (HPMC);calcium carbonate; glycine; bentonite; block co-polymers;polyvinylpyrrolidone; and the like. Such carriers or diluents, ifpresent, constitute in total about 5% to about 99%, preferably about 10%to about 85%, and more preferably about 20% to about 80%, of the totalweight of the composition. The carrier, carriers, diluent, or diluentsselected preferably exhibit suitable flow properties and, where tabletsare desired, compressibility.

Lactose, mannitol, dibasic sodium phosphate, and microcrystallinecellulose (particularly Avicel PH microcrystalline cellulose such asAvicel PH 101), either individually or in combination, are preferreddiluents. These diluents are chemically compatible with celecoxib. Theuse of extragranular microcrystalline cellulose (that is,microcrystalline cellulose added to a granulated composition) can beused to improve hardness (for tablets) and/or disintegration time.Lactose, especially lactose monohydrate, is particularly preferred.Lactose typically provides compositions having suitable release rates ofcelecoxib, stability, pre-compression flowability, and/or dryingproperties at a relatively low diluent cost. It provides a high densitysubstrate that aids densification during granulation (where wetgranulation is employed) and therefore improves blend flow propertiesand tablet properties.

Pharmaceutical compositions of the invention optionally comprise one ormore pharmaceutically acceptable disintegrants as excipients,particularly for tablet formulations. Suitable disintegrants include,but are not limited to, either individually or in combination, starches,including sodium starch glycolate (e.g., Explotab™ of PenWest) andpregelatinized corn starches (e.g., National™ 1551 of National Starchand Chemical Company, National™ 1550, and Colorcon™ 1500), clays (e.g.,Veegum™ HV of R.T. Vanderbilt), celluloses such as purified cellulose,microcrystalline cellulose, methylcellulose, carboxymethylcellulose andsodium carboxymethylcellulose, croscarmellose sodium (e.g., Ac-Di-Sol™of FMC), alginates, crospovidone, and gums such as agar, guar, locustbean, karaya, pectin and tragacanth gums.

Disintegrants may be added at any suitable step during the preparationof the composition, particularly prior to granulation or during alubrication step prior to compression. Such disintegrants, if present,constitute in total about 0.2% to about 30%, preferably about 0.2% toabout 10%, and more preferably about 0.2% to about 5%, of the totalweight of the composition.

Croscarmellose sodium is a preferred disintegrant for tablet or capsuledisintegration, and, if present, preferably constitutes about 0.2% toabout 10%, more preferably about 0.2% to about 7%, and still morepreferably about 0.2% to about 5%, of the total weight of thecomposition. Croscarmellose sodium confers superior intragranulardisintegration capabilities to granulated pharmaceutical compositions ofthe present invention.

Pharmaceutical compositions of the invention optionally comprise one ormore pharmaceutically acceptable binding agents or adhesives asexcipients, particularly for tablet formulations. Such binding agentsand adhesives preferably impart sufficient cohesion to the powder beingtableted to allow for normal processing operations such as sizing,lubrication, compression and packaging, but still allow the tablet todisintegrate and the composition to be absorbed upon ingestion. Suchbinding agents may also prevent or inhibit crystallization orrecrystallization of a celecoxib salt of the present invention once thesalt has been dissolved in a solution. Suitable binding agents andadhesives include, but are not limited to, either individually or incombination, acacia; tragacanth; sucrose; gelatin; glucose; starchessuch as, but not limited to, pregelatinized starches (e.g., National™1511 and National™ 1500); celluloses such as, but not limited to,methylcellulose and carmellose sodium (e.g., Tylose™); alginic acid andsalts of alginic acid; magnesium aluminum silicate; PEG; guar gum;polysaccharide acids; bentonites; povidone, for example povidone K-15,K-30 and K-29/32; polymethacrylates; HPMC; hydroxypropylcellulose (e.g.,Klucel™ of Aqualon); and ethylcellulose (e.g., Ethocel™ of the DowChemical Company). Such binding agents and/or adhesives, if present,constitute in total about 0.5% to about 25%, preferably about 0.75% toabout 15%, and more preferably about 1% to about 10%, of the totalweight of the pharmaceutical composition.

Many of the binding agents are polymers comprising amide, ester, ether,alcohol or ketone groups and, as such, are preferably included inpharmaceutical compositions of the present invention.Polyvinylpyrrolidones such as povidone K-30 are especially preferred.Polymeric binding agents can have varying molecular weight, degrees ofcrosslinking, and grades of polymer. Polymeric binding agents can alsobe copolymers, such as block co-polymers that contain mixtures ofethylene oxide and propylene oxide units. Variation in these units'ratios in a given polymer affects properties and performance. Examplesof block co-polymers with varying compositions of block units arePoloxamer 188 and Poloxamer 237 (BASF Corporation).

Pharmaceutical compositions of the invention optionally comprise one ormore pharmaceutically acceptable wetting agents as excipients.Non-limiting examples of surfactants that can be used as wetting agentsin pharmaceutical compositions of the invention include quaternaryammonium compounds, for example benzalkonium chloride, benzethoniumchloride and cetylpyridinium chloride, dioctyl sodium sulfosuccinate,polyoxyethylene alkylphenyl ethers, for example nonoxynol 9, nonoxynol10, and octoxynol 9, poloxamers (polyoxyethylene and polyoxypropyleneblock copolymers), polyoxyethylene fatty acid glycerides and oils, forexample polyoxyethylene (8) caprylic/capric mono- and diglycerides(e.g., Labrasol™ of Gattefosse), polyoxyethylene (35) castor oil andpolyoxyethylene (40) hydrogenated castor oil; polyoxyethylene alkylethers, for example polyoxyethylene (20) cetostearyl ether,polyoxyethylene fatty acid esters, for example polyoxyethylene (40)stearate, polyoxyethylene sorbitan esters, for example polysorbate 20and polysorbate 80 (e.g., Tween™ 80 of ICI), propylene glycol fatty acidesters, for example propylene glycol laurate (e.g., Lauroglycol™ ofGattefosse), sodium lauryl sulfate, fatty acids and salts thereof, forexample oleic acid, sodium oleate and triethanolamine oleate, glycerylfatty acid esters, for example glyceryl monostearate, sorbitan esters,for example sorbitan monolaurate, sorbitan monooleate, sorbitanmonopalmitate and sorbitan monostearate, tyloxapol, and mixturesthereof. Such wetting agents, if present, constitute in total about0.25% to about 15%, preferably about 0.4% to about 10%, and morepreferably about 0.5% to about 5%, of the total weight of thepharmaceutical composition.

Wetting agents that are anionic surfactants are preferred. Sodium laurylsulfate is a particularly preferred wetting agent. Sodium laurylsulfate, if present, constitutes about 0.25% to about 7%, morepreferably about 0.4% to about 4%, and still more preferably about 0.5%to about 2%, of the total weight of the pharmaceutical composition.

Pharmaceutical compositions of the invention optionally comprise one ormore pharmaceutically acceptable lubricants (including anti-adherentsand/or glidants) as excipients. Suitable lubricants include, but are notlimited to, either individually or in combination, glyceryl behapate(e.g., Compritol™ 888 of Gattefosse); stearic acid and salts thereof,including magnesium, calcium and sodium stearates; hydrogenatedvegetable oils (e.g., Sterotex™ of Abitec); colloidal silica; talc;waxes; boric acid; sodium benzoate; sodium acetate; sodium fumarate;sodium chloride; DL-leucine; PEG (e.g., Carbowax™ 4000 and Carbowax™6000 of the Dow Chemical Company); sodium oleate; sodium lauryl sulfate;and magnesium lauryl sulfate. Such lubricants, if present, constitute intotal about 0.1% to about 10%, preferably about 0.2% to about 8%, andmore preferably about 0.25% to about 5%, of the total weight of thepharmaceutical composition.

Magnesium stearate is a preferred lubricant used, for example, to reducefriction between the equipment and granulated mixture during compressionof tablet formulations.

Suitable anti-adherents include, but are not limited to, talc,cornstarch, DL-leucine, sodium lauryl sulfate and metallic stearates.Talc is a preferred anti-adherent or glidant used, for example, toreduce formulation sticking to equipment surfaces and also to reducestatic in the blend. Talc, if present, constitutes about 0.1% to about10%, more preferably about 0.25% to about 5%, and still more preferablyabout 0.5% to about 2%, of the total weight of the pharmaceuticalcomposition.

Glidants can be used to promote powder flow of a solid formulation.Suitable glidants include, but are not limited to, colloidal silicondioxide, starch, talc, tribasic calcium phosphate, powdered celluloseand magnesium trisilicate. Colloidal silicon dioxide is particularlypreferred.

Other excipients such as colorants, flavors and sweeteners are known inthe pharmaceutical art and can be used in pharmaceutical compositions ofthe present invention. Tablets can be coated, for example with anenteric coating, or uncoated. Compositions of the invention can furthercomprise, for example, buffering agents.

Optionally, one or more effervescent agents can be used as disintegrantsand/or to enhance organoleptic properties of pharmaceutical compositionsof the invention. When present in pharmaceutical compositions of theinvention to promote dosage form disintegration, one or moreeffervescent agents are preferably present in a total amount of about30% to about 75%, and preferably about 45% to about 70%, for exampleabout 60%, by weight of the pharmaceutical composition.

According to a particularly preferred embodiment of the invention, aneffervescent agent, present in a solid dosage form in an amount lessthan that effective to promote disintegration of the dosage form,provides improved dispersion of the celecoxib in an aqueous medium.Without being bound by theory, it is believed that the effervescentagent is effective to accelerate dispersion of the drug, such ascelecoxib, from the dosage form in the gastrointestinal tract, therebyfurther enhancing absorption and rapid onset of therapeutic effect. Whenpresent in a pharmaceutical composition of the invention to promoteintragastrointestinal dispersion but not to enhance disintegration, aneffervescent agent is preferably present in an amount of about 1% toabout 20%, more preferably about 2.5% to about 15%, and still morepreferably about 5% to about 10%, by weight of the pharmaceuticalcomposition.

An “effervescent agent” herein is an agent comprising one or morecompounds which, acting together or individually, evolve a gas oncontact with water. The gas evolved is generally oxygen or, mostcommonly, carbon dioxide. Preferred effervescent agents comprise an acidand a base that react in the presence of water to generate carbondioxide gas. Preferably, the base comprises an alkali metal or alkalineearth metal carbonate or bicarbonate and the acid comprises an aliphaticcarboxylic acid.

Non-limiting examples of suitable bases as components of effervescentagents useful in the invention include carbonate salts (e.g., calciumcarbonate), bicarbonate salts (e.g., sodium bicarbonate),sesquicarbonate salts, and mixtures thereof. Calcium carbonate is apreferred base.

Non-limiting examples of suitable acids as components of effervescentagents and/or solid organic acids useful in the invention include citricacid, tartaric acid (as D-, L-, or D/L-tartaric acid), malic acid,maleic acid, fumaric acid, adipic acid, succinic acid, acid anhydridesof such acids, acid salts of such acids, and mixtures thereof Citricacid is a preferred acid.

In a preferred embodiment of the invention, where the effervescent agentcomprises an acid and a base, the weight ratio of the acid to the baseis about 1:100 to about 100:1, more preferably about 1:50 to about 50:1,and still more preferably about 1:10 to about 10:1. In a furtherpreferred embodiment of the invention, where the effervescent agentcomprises an acid and a base, the ratio of the acid to the base isapproximately stoichiometric.

Excipients which solubilize metal salts of drugs like celecoxibtypically have both hydrophilic and hydrophobic regions, or arepreferably amphiphilic or have amphiphilic regions. One type ofamphiphilic or partially-amphiphilic excipient comprises an amphiphilicpolymer or is an amphiphilic polymer. A specific amphiphilic polymer isa polyalkylene glycol, which is commonly comprised of ethylene glycoland/or propylene glycol subunits. Such polyalkylene glycols can beesterified at their termini by a carboxylic acid, ester, acid anhyrideor other suitable moiety. Examples of such excipients include poloxamers(symmetric block copolymers of ethylene glycol and propylene glycol;e.g., poloxamer 237), polyalkyene glycolated esters of tocopherol(including esters formed from a di- or multi-functional carboxylic acid;e.g., d-alpha-tocopherol polyethylene glycol-1000 succinate), andmacrogolglycerides (formed by alcoholysis of an oil and esterificationof a polyalkylene glycol to produce a mixture of mono-, di- andtri-glycerides and mono- and di-esters; e.g., stearoyl macrogol-32glycerides). Such pharmaceutical compositions are advantageouslyadministered orally.

Solid dosage forms of the invention can be prepared by any suitableprocess, not limited to processes described herein.

An illustrative process comprises (a) a step of blending a celecoxibsalt of the invention with one or more excipients to form a blend, and(b) a step of tableting or encapsulating the blend to form tablets orcapsules, respectively.

In a preferred process, solid dosage forms are prepared by a processcomprising (a) a step of blending a drug salt such as a celecoxib saltof the invention with one or more excipients to form a blend, (b) a stepof granulating the blend to form a granulate, and (c) a step oftableting or encapsulating the blend to form tablets or capsulesrespectively. Step (b) can be accomplished by any dry or wet granulationtechnique known in the art, but is preferably a dry granulation step. Asalt of the present invention is advantageously granulated to formparticles of about 1 micrometer to about 100 micrometer, about 5micrometer to about 50 micrometer, or about 10 micrometer to about 25micrometer. One or more diluents, one or more disintegrants and one ormore binding agents are preferably added, for example in the blendingstep, a wetting agent can optionally be added, for example in thegranulating step, and one or more disintegrants are preferably addedafter granulating but before tableting or encapsulating. A lubricant ispreferably added before tableting. Blending and granulating can beperformed independently under low or high shear. A process is preferablyselected that forms a granulate that is uniform in drug content, thatreadily disintegrates, that flows with sufficient ease so that weightvariation can be reliably controlled during capsule filling ortableting, and that is dense enough in bulk so that a batch can beprocessed in the selected equipment and individual doses fit into thespecified capsules or tablet dies.

In an alternative embodiment, solid dosage forms are prepared by aprocess that includes a spray drying step, wherein a celecoxib salt issuspended with one or more excipients in one or more sprayable liquids,preferably a non-protic (e.g., non-aqueous or non-alcoholic) sprayableliquid, and then is rapidly spray dried over a current of warm air.

A granulate or spray dried powder resulting from any of the aboveillustrative processes can be compressed or molded to prepare tablets orencapsulated to prepare capsules.

Conventional tableting and encapsulation techniques known in the art canbe employed. Where coated tablets are desired, conventional coatingtechniques are suitable.

Excipients for tablet compositions of the invention are preferablyselected to provide a disintegration time of less than about 30 minutes,preferably about 25 minutes or less, more preferably about 20 minutes orless, and still more preferably about 15 minutes or less, in a standarddisintegration assay.

Celecoxib dosage forms of the invention preferably comprise celecoxib ina daily dosage amount of about 10 mg to about 1000 mg, more preferablyabout 25 mg to about 400 mg, and most preferably about 50 mg to about200 mg.

In a further embodiment the PG solvate comprises an API from Table 3.For APIs in Table 3 listed as salts, solvates, hydrates, and the like,the PG solvate can either be of the form listed in Table 3 or a PGsolvate of the free form, or a PG solvate of another form that is notlisted. Table 3 includes the CAS number, chemical name or a PCT orpatent reference (each incorporated herein in their entireties). Inanother embodiment, any one or more of the APIs of Table 3 may bespecifically excluded from the present invention. Any APIs currentlyknown in the art may also be specifically excluded from the presentinvention. For example, azithromycin and cephalosporin may bespecifically excluded from the present invention.

EXEMPLIFICATION Procedure for Raman Acquisition Acquisition

The sample was either left in the glass vial in which it was processedor an aliquot of the sample was transferred to a glass slide. The glassvial or slide was positioned in the sample chamber. The measurement wasmade using an Almega™ Dispersive Raman (Almega™ Dispersive Raman,Thermo-Nicolet, 5225 Verona Road, Madison, Wis. 53711-4495) systemfitted with a 785 nm laser source. The sample was manually brought intofocus using the microscope portion of the apparatus with a 10× powerobjective (unless otherwise noted), thus directing the laser onto thesurface of the sample. The spectrum was acquired using the parametersoutlined in Table 1. (Exposure times and number of exposures may vary;changes to parameters will be indicated for each acquisition.)

TABLE 2 Raman Spectral acquisition parameters Parameter Setting UsedExposure time (s) 2.0 Number of exposures 10 Laser source wavelength 785(nm) Laser power (%) 100 Aperture shape pin hole Aperture size (um) 100Spectral range 104-3428 Grating position Single Temperature atacquisition 24.0 (degrees C.)

Procedure for Powder X-Ray Diffraction (PXRD)

All powder x-ray diffraction patterns were obtained using the D/MaxRapid X-ray Diffractometer (D/Max Rapid, Contact Rigaku/MSC, 9009 NewTrails Drive, The Woodlands, Tex., USA 77381-5209) equipped with acopper source (Cu/K_(α)□1.5406 Å), manual x-y stage, and 0.3 mmcollimator, unless otherwise indicated. The sample was loaded into a 0.3mm boron rich glass capillary tube (e.g., Charles Supper Company, 15Tech Circle, Natick Mass. 01760-1024) by sectioning off one end of thetube and tapping the open, sectioned end into a bed of the powderedsample or into the sediment of a slurried precipitate. Note, precipitatecan be amorphous or crystalline. The loaded capillary was mounted in aholder that was secured into the x-y stage. A diffractogram was acquired(e.g., Control software: RINT Rapid Control Software, Rigaku Rapid/XRD,version 1.0.0, © 1999 Rigaku Co.) under ambient conditions at a powersetting of 46 kV at 40 mA in reflection mode, while oscillating aboutthe omega-axis from 0-5 degrees at 1 degree/s and spinning about thephi-axis at 2 degrees/s. The exposure time was 15 minutes unlessotherwise specified. The diffractogram obtained was integrated over2-theta from 2-60 degrees and chi (1 segment) from 0-360 degrees at astep size of 0.02 degrees using the cyllnt utility in the RINT Rapiddisplay software (Analysis software: RINT Rapid display software,version 1.18, Rigaku/MSC.) provided by Rigaku with the instrument. Thedark counts value was set to 8 as per the system calibration (Systemset-up and calibration by Rigaku); normalization was set to average; theomega offset was set to 180°; and no chi or phi offsets were used forthe integration. The analysis software JADE XRD Pattern. Processing,versions 5.0 and 6.0 ((⁸1995-2002, Materials Data, Inc. was also used.

The relative intensity of peaks in a diffractogram is not necessarily alimitation of the PXRD pattern because peak intensity can vary fromsample to sample, e.g., due to crystalline impurities. Further, theangles of each peak can vary by about +/−0.1 degrees, preferably+/−0.05. The entire pattern or most of the pattern peaks may also shiftby about +/−0.1 degree due to differences in calibration, settings, andother variations from instrument to instrument and from operator tooperator. The above limitations result in a PXRD error of +/−0.1 degrees2-theta for each diffraction peak.

Procedure for Differential Scanning Calorimetry (DSC)

An aliquot of the sample was weighed into an aluminum sample pan. (e.g.,Pan part #900786.091; lid part #900779.901; TA Instruments, 109 LukensDrive, New Castle, Del. 19720) The sample pan was sealed either bycrimping for dry samples or press fitting for wet samples (e.g.,hydrated or solvated samples). The sample pan was loaded in to theapparatus (DSC: Q1000 Differential Scanning Calorimeter, TA Instruments,109 Lukens Drive, New Castle, Del. 19720), which is equipped with anauto sampler, and a thermogram was obtained by individually heating thesample (e.g., Control software: Advantage for QW-Series, version1.0.0.78, Thermal Advantage Release 2.0, © 2001 TA instruments—WaterLLC) at a rate of 10 degrees C. /min from T_(min) (typically 20 degreesC.) to T_(max) (typically 300 degrees C.) (Heating rate and temperaturerange may vary, changes to these parameters will be indicated for eachsample) using an empty aluminum pan as a reference. Dry nitrogen (e.g.,Compressed nitrogen, grade 4.8, BOC Gases, 575 Mountain Avenue, MurrayHill, N.J. 07974-2082) was used as a sample purge gas and was set at aflow rate of 50 mL/min. Thermal transitions were viewed and analyzedusing the analysis software (Analysis Software: Universal Analysis 2000for Windows 95/95/2000/NT, version 3.1E; Build 3.1.0.40, © 1991-2001TAinstruments—Water LLC) provided with the instrument.

Procedure for Thermogravimetric Analysis (TGA)

An aliquot of the sample was transferred into a platinum sample pan.(Pan part #952019.906; TA Instruments, 109 Lukens Drive, New Castle,Del. 19720) The pan was placed on the loading platform and was thenautomatically loaded in to the apparatus (TGA: Q500 ThermogravimetricAnalyzer, TA Instruments, 109 Lukens Drive, New Castle, Del. 19720)using the control software (Control software: Advantage for QW-Series,version 1.0.0.78, Thermal Advantage Release 2.0, © 2001 TAinstruments—Water LLC). Thermograms were obtained by individuallyheating the sample at 10 degrees C. /min from 25 degrees C. to 300degrees C. (Heating rate and temperature range may vary, changes inparameters will be indicated for each sample) under flowing dry nitrogen(e.g., Compressed nitrogen, grade 4.8, BOC Gases, 575 Mountain Avenue,Murray Hill, N.J. 07974-2082), with a sample purge flow rate of 60mL/min and a balance purge flow rate of 40 mL/min. Thermal transitions(e.g. weight changes) were viewed and analyzed using the analysissoftware (Analysis Software: Universal Analysis 2000 for Windows95/95/2000/NT, version 3.1E; Build 3.1.0.40, ® 1991-2001TAinstruments—Water LLC) provided with the instrument.

Example 1 Celecoxib Sodium Salt PG Solvate

A propylene glycol solvate of the sodium salt of celecoxib was prepared.To a solution of celecoxib (312 mg; 0.818 mmol) in diethyl ether (6 mL)was added propylene glycol (0.127 mL, 1.73 mmol). To the clear solutionwas added sodium ethoxide in ethanol (21%, 0.275 mL, 0.817 mmol). After1 minute, crystals began to form. After 5 minutes, the solid hadcompletely crystallized. The solid was collected by filtration and waswashed with additional diethyl ether (10 mL). The off-white solid wasthen air-dried and collected. The crystalline salt form was identifiedas a 1:1 solvate of propylene glycol. The solid was characterized by TGAand PXRD. The results are depicted in FIGS. 1 and 2A.

FIG. 1 shows the results of TGA. A weight loss of about 15.6% wasobserved between about 65 and 200 degrees C. which represents 1 molarequivalent of propylene glycol to celecoxib Na salt. FIG. 2A shows theresults of PXRD. Peaks, in 2-theta angles, that can be used tocharacterize the solvate include any 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 ofthe following: 3.77, 7.57, 8.21, 11.33, 14.23, 16.13, 18.69, 20.65,22.69 and 24.77 degrees or any one or any combination of 1, 2, 3, 4, 5,6, 7, 8, 9, 10, or more peaks of FIG. 2A. The TGA thermogram or PXRDdiffractogram data may be used alone or in any combination tocharacterize the solvate. A 0.8 mm collimator was used duringacquisition of the diffractogram.

Several closely related, yet distinguishable, PXRD diffractograms havebeen obtained by performing the above synthesis several times. FIGS. 2B,2C, and 2D are additional diffractograms of the propylene glycol solvateof celecoxib sodium salt. A comparison of these diffractograms yields anumber of noticeable differences. For example, the peak at 8.21 degrees2-theta in FIG. 2A is not present in FIG. 2B or 2C. Another peak at 8.79degrees 2-theta, present in FIGS. 2B and 2D, is not found in FIG. 2A or2C. Other distinctions can also be found between the fourdiffractograms. Such distinctions in otherwise similar diffractogramssuggest the existence of polymorphism or perhaps a variable hydrate.

In another embodiment of the present invention, a PG solvate of an APIcan give rise to distinct PXRD diffractograms. This can be caused bypolymorphism, a variable hydrate, a different environmental condition,etc. In one embodiment, the propylene glycol solvate of celecoxib sodiumsalt can yield a PXRD pattern with the absence or presence of a peak at8.21 degrees 2-theta. In another embodiment, the propylene glycolsolvate of celecoxib sodium salt can yield a PXRD pattern with theabsence or presence of a peak at 8.79 degrees 2-theta.

Example 2 Celecoxib Potassium Salt PG Solvate

A propylene glycol solvate of the potassium salt of celecoxib wasprepared. To a solution of celecoxib (253 mg, 0.664 mmol) in diethylether (6 mL) was added propylene glycol (0.075 mL, 1.02 mmol). To theclear solution was added potassium t-butoxide in tetrahydrofuran (THF)(1 M, 0.66 mL, 0.66 mmol). Crystals immediately began to form. After 5minutes, the solid had completely crystallized. The solid was collectedby filtration and was washed with additional diethyl ether (10 mL). Thewhite solid was then air-dried and collected. The crystalline salt formwas found to be a 1:1 propylene glycol solvate of celecoxib K salt. Thesolid was characterized by TGA and PXRD. The results are depicted inFIGS. 3 and 4.

FIG. 3 shows the results of TGA. A weight loss of about 14.94% wasobserved between about 65 and about 250 degrees C. which is consistentwith 1 molar equivalent of propylene glycol to celecoxib K. FIG. 4 showsthe results of PXRD. Peaks, in 2-theta angles, that can be used tocharacterize the solvate include any 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 ofthe following: 3.75, 7.47, 11.33, 14.89, 15.65, 18.31, 20.49, 21.73,22.51, and 24.97 degrees or any one or any combination of 1, 2, 3, 4, 5,6, 7, 8, 9, 10, or more peaks of FIG. 4.

Example 3 Celecoxib Lithium Salt PG Solvate

A propylene glycol solvate of the lithium salt of celecoxib wasprepared. To a solution of celecoxib (264 mg, 0.693 mmol) in diethylether (8 mL) was added propylene glycol (0.075 mL, 1.02 mmol), To theclear solution was added t-butyl lithium in pentane (1.7 M, 0.40 mL,0.68 mmol). A brown solid formed immediately but dissolved within oneminute which subsequently yielded a white fluffy solid. The white solidcrystallized completely after 10 minutes. The solid was collected byfiltration and was washed with additional diethyl ether (10 mL). Thewhite solid was then air-dried and collected. The crystalline salt formwas found to be a 1:1 propylene glycol solvate of celecoxib Li. Thesolid was characterized by TGA and PXRD.

The results of TGA are depicted in FIG. 5 and show a weight loss ofabout 16.3% between 50 degrees C. and 210 degrees C. which is consistentwith 1 molar equivalent of propylene glycol to celecoxib Li. The resultsof PXRD are shown in FIG. 6. Characteristic peaks of 2-theta angles thatcan be used to characterize the salt include any one, or combination ofany 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 of 3.79, 7.51, 8.19, 9.83,11.41, 15.93, 18.29, 19.19, 19.87, 20.63, 22.01, or 25.09 degrees or anyone or any combination of peaks of FIG. 6.

Example 4

Naproxen Sodium Salt PG Solvate

A propylene glycol solvate of a sodium salt of naproxen was prepared. Toa solution of naproxen (348 mg, 1.51 mmol) in diethyl ether (10 mL) wasadded propylene glycol (0.200 ml, 2.72 mmol). To the clear solution wasadded sodium ethoxide in ethanol (21%, 0.750 mL, 2.01 mmol). Thesolution became slightly yellow due to the sodium ethoxide. After 1minute, crystals began to form. After 5 minutes, the solid hadcompletely crystallized. The solid was collected by filtration and waswashed with diethyl ether (10 mL) The product was then air-dried andcollected. The solvate was 2:1 naproxen Na:propylene glycol. The solidwas characterized by TGA and PXRD.

The TGA thermogram of naproxen sodium salt PG solvate is shown in FIG.7, and indicates a 13.5 percent weight loss between about 75 and 150degrees C. This weight loss is consistent with a 2:1 naproxenNa:propylene glycol solvate. The PXRD diffractogram of naproxen sodiumsalt PG solvate is shown in FIG. 8, and shows peaks at 2-theta angles,including but not limited to, 6.67, 9.65, 13.41, 15.77, 18.55, 20.83,22.79, and 27.17 degrees. Any one, any two, any three, any four, anyfive, any six, any seven, or all eight of the above peaks or any one orany combination of peaks in FIG. 8 can be used to characterize naproxensodium salt PG solvate.

Example 5 Preparation Of Olanzapine PG Solvate

Olanzapine PG solvate was prepared by dissolving 1.05 g of olanzapineform I in 8 mL of isopropylacetate and 2.0 mL of propylene glycol withheating. The hot liquid was filtered through a 0.2 micrometer nylonsyringe filter. Crystallization occurred after cooling to roomtemperature. The addition of a small amount of seed crystals from aprevious reaction followed by sonication for 10 seconds also facilitatedcrystallization. Olanzapine PG solvate was isolated by suctionfiltration, rinsed with isopropylacetate and allowed to air dry. Theproduct was a fine yellow powder. The crystals grew in three dimensions,yielding chunks.

A second preparation of olanzapine form I PG solvate was completed bydissolving 16.2 mg of olanzapine form I in 0.05 ml of propylene glycoland 0.05 ml of isopropylacetate with heating. The sample was cooled toroom temperature and a single crystal from a previous preparation wasadded. The sample was allowed to sit undisturbed for 2 days during whichan aggregate clump of several large crystals grew. The crystals weretransferred to filter paper, rinsed with a single drop ofisopropylacetate, and dried by dabbing with the filter paper. The rinseprocedure was repeated a total of four times with fresh filter paper.Characterization of the product has been achieved via TGA, DSC, PXRD,and Raman spectroscopy.

Results from TGA analysis show an 18.05% weight loss representing lossof about 1 equivalent of propylene glycol (FIG. 9). Results from DSCshow a peak endothermic transition at 92.63 degrees C. (FIG. 10).

The PXRD pattern has characteristic peaks as shown for two samplepreparations in FIGS. 11A and 11B. Peaks can be seen at 2-theta anglesincluding but not limited to 8.33, 8.95, 11.75, 14.47, 15.61, 17.95,19.21, 19.57, 20.65, 21.41, 22.03, and 23.29 in FIG. 11A. The crystalcan be characterized by any one, any two, any three, any four, any 5,any 6, any 7, any 8, any 9, any 10, any 11, or all 12 of the peaks aboveor one or a combination of peaks in FIG. 11A. In the secondrepresentative sample, peaks can be seen at 2-theta angles including,but not limited to, 8.39, 8.89, 13.95, 14.45, 15.55, 17.91, 19.13,19.55, 20.61, 21.47, 22.07, and 23.31 in FIG. 11B. The crystal can becharacterized by any one, any two, any three, any four, any 5, any 6,any 7, any 8, any 9, any 10, any 11, or all 12 of the peaks above or oneor a combination of peaks in FIG. 11B.

Single-crystal x-ray studies of olanzapine form I PG solvate were alsocompleted. FIG. 12 shows a packing diagram of the single-crystalstructure of olanzapine form I PG solvate. The unit cell data are asfollows: space group P2(1)/c, A=10.4264(9), B=13.3916(11),C=14.4424(12), Alpha=90, Beta=95.503(2), Gamma=90, Volume=2007.2(3).

Example 6 Preparation of Cortisone Acetate PG Solvate

Cortisone acetate PG solvate was prepared by dissolving 9.7 mg cortisoneacetate in 0.6 mL propylene glycol with heating. Needle-like crystalsformed upon cooling, followed by the conversion to large, very thin,rectangular plates over a couple hours.

A second preparation of cortisone acetate PG solvate was completed bydissolving 11.9 mg cortisone acetate in 0.7 mL isopropylacetate withheating to reflux. Upon crystal formation, 0.05 mL propylene glycol wasadded, heated to reflux to dissolve, and crystals again formed. Theresultant crystals were collected and analyzed by PXRD, TGA, and DSC.

A third preparation of cortisone acetate PG solvate was completed bydissolving 65.8 mg cortisone acetate in 7.0 mL isopropylacetate and 0.05mL propylene glycol with heating. The mixture was cooled slightly andseed crystals from a previous reaction (second preparation above) wereadded. The resultant crystals form rods, or long rectangular plates thatare birefringent when viewed by plane polarized microscopy. Crystalswere harvested after 30 minutes and analyzed by single crystal x-ray.Prior to PXRD measurement, the sample was ground, transferred to a vial,and left open to the atmosphere for 4 days.

Results from TGA analysis show a 15.9% weight loss at temperatures up to150 degrees C. (FIG. 13). 14.9% weight loss occurred between 70 and 150degrees C. while up to 1.2% weight loss occurred at lower temperatures.This weight loss is representative of a cortisone acetate PG solvatewith 1.0 equivalents of propylene glycol. DSC was completed in a closed,not sealed aluminium pan from room temperature to 300 degrees C. at 10degrees/minute (FIG. 14). The compound was discovered to have twoendothermic transitions, one at 148 degrees C. with an intensity of 146J/g, and the second at 237 degrees C. with an intensity of 77 J/g.

The PXRD of cortisone acetate PG solvate crystallized fromisopropylacetate/propylene glycol solution is shown in twodiffractograms in FIG. 15A and FIG. 15B. Peaks can be seen at 2-thetaangles including, but not limited to, 5.31, 10.71, 14.54, 15.66, 18.49,21.33, and 23.49 degrees. The crystal can be characterized by any one,any two, any three, any four, any five, any six, or any seven, or anycombination of the peaks listed above or one or a combination of peakslisted in FIG. 15A. In the second representative sample, peaks can beseen at 2-theta angles including, but not limited to, 5.29, 10.73,14.57, 15.69, 18.51, 21.39, 23.51, and 27.49 in FIG. 15B. The crystalcan be characterized by any one, any two, any three, any four, any 5,any 6, any 7, or all 8 of the peaks above or one or a combination ofpeaks in FIG. 15B. FIG. 16 shows a PXRD diffractogram of materialcrystallized from isopropylacetate alone. This is provided only todifferentiate the PG solvate from the unsolvated form of the API.

Single-crystal x-ray studies of cortisone acetate PG solvate were alsocompleted. FIG. 17 shows a packing diagram of the single-crystalstructure of cortisone acetate PG solvate. The unit cell data are asfollows: space group P2(1), A=9.728(2), B=7.6306(15), C=16.454(3),Alpha=90, Beta=92.568(4), Gamma=90, Volume=1220.2(4).

Example 7 Celecoxib Sodium PG Solvate Trihydrate Preparation:

Celecoxib Na propylene glycol trihydrate was formed by allowing thecelecoxib sodium salt propylene glycol solvate to sit at 60% RH and 20degrees C. for 3 days. (Note: Formation of the trihydrate at 75% and 40degrees C. occurs as well). The trihydrate begins to form somewherebetween 31 and 40% RH at room temperature.

The solid was characterized by TGA and PXRD, which are shown in FIGS. 18and 19, respectively. FIG. 18 shows the results of the TGA where 9.64%weight loss was observed between room temperature and 60 degrees C. and13.6% weight loss was observed between 60 degrees C. and 175 degrees C.The PXRD pattern has characteristic peaks at 2-theta angles shown inFIG. 19. Any 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more peaks can be used tocharacterize the trihydrate, including for example, peaks at 3.47, 6.97,10.37, 13.97, 16.41, 19.45, 21.29, 22.69, 23.87, and 25.75 degrees. A0.8 mm collimator was used during acquisition of the diffractogram.

The trihydrate can also be formed by crystallization of celecoxib Napropylene glycol solvate in the presence of H₂O. To a solution ofcelecoxib (136.2 mg; 0.357 mmol) in diethyl ether (6.0 mL), water (0.025mL; 1.39 mmol), and propylene glycol (0.030 mL; 0.408 mmol) was addedsodium ethoxide in ethanol (21 wt. %; 0.135 mL; 0.362 mmol). A solidformed within one minute and was isolated via filtration. The solid wasthen washed with additional diethyl ether (2.0 mL) and allowed to airdry. This procedure gives essentially the same PXRD pattern but there isa slight excess of water, which is probably surface water.

The solid was characterized by TGA and PXRD, which are shown in FIGS. 20and 21, respectively. FIG. 20 shows the results of TGA where 10.92%weight loss was observed between room temperature and 50 degrees C. and12.95% weight loss was observed between 50 degrees C. and 195 degrees C.The PXRD pattern has characteristic peaks at 2-theta angles shown inFIG. 21. Any 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or more peaks can beused to characterize the trihydrate, including for example, peaks at3.43, 6.95, 10.25, 13.95, 16.39, 17.39, 17.75, 18.21, 19.43, 21.21,22.61, and 25.71 degrees. A 0.8 mm collimator was used duringacquisition of the diffractogram.

FIGS. 22-24 have been included as reference PXRD diffractograms. FIG. 22shows the PXRD diffractogram of celecoxib sodium salt. FIG. 23 shows thePXRD diffractogram of celecoxib lithium salt. FIG. 24 shows the PXRDdiffractogram of celecoxib potassium salt. Dynamic moisture sorptionstudies of several embodiments of the present invention have beendiscussed in PCT/US03/XXXXX filed on Dec. 24, 2003, entitled“Pharmaceutical Compositions With Improved Dissolution” (Attorney DocketNo. TPI-1700CXC2 PCT) by Tawa et al, which is hereby incorporated byreference, in its entirety. Dynamic moisture sorption studies can beused to illustrate important characteristics of the solvates of thepresent invention, such as decreased hygroscopicity or increased formstability.

While this invention has been particularly shown and described withreferences to preferred embodiments thereof, it will be understood bythose skilled in the art that various changes in form and details may bemade therein without departing from the scope of the inventionencompassed by the appended claims.

Lengthy table referenced here US20100279993A1-20101104-T00001 Pleaserefer to the end of the specification for access instructions.

LENGTHY TABLES The patent application contains a lengthy table section.A copy of the table is available in electronic form from the USPTO website(http://seqdata.uspto.gov/?pageRequest=docDetail&DocID=US20100279993A1).An electronic copy of the table will also be available from the USPTOupon request and payment of the fee set forth in 37 CFR 1.19(b)(3).

1. A pharmaceutical composition comprising a form of a propylene glycolsolvate of an active pharmaceutical ingredient (API) selected fromolanzapine, cortisone acetate, naproxen, celecoxib trihydrate, celecoxibor salts thereof.
 2. The composition according to claim 1, wherein theAPI is olanzapine and the composition is characterized by a powder x-raydiffraction (PXRD) pattern comprising peaks expressed in terms of2-theta angles, wherein: a) said form is a propylene glycol solvate ofolanzapine and said PXRD pattern comprises peaks at 8.33, 15.61, and21.41 degrees; or b) said form is a propylene glycol solvate ofolanzapine and said PXRD pattern comprises peaks at 8.95, 14.47, 22.03,and 23.29 degrees; or c) said form is a propylene glycol solvate ofolanzapine and said PXRD pattern comprises peaks at 14.47, 17.95, 19.57,and 20.65 degrees; or d) said form is a propylene glycol solvate ofolanzapine and said PXRD pattern comprises peaks at 8.33, 8.95, 14.47,15.61, 17.95, and 23.29 degrees; or f) said form is a propylene glycolsolvate of olanzapine and said PXRD pattern comprises peaks at 14.47,15.61, and 20.65 degrees; or g) said form is a propylene glycol solvateof olanzapine and said PXRD pattern comprises peaks at 8.33 and 21.41degrees; or h) said form is a propylene glycol solvate of olanzapine andsaid PXRD pattern comprises a peak at 14.47 degrees; or i) said form isa propylene glycol solvate of olanzapine and said PXRD pattern comprisespeaks at 14.47 and 22.03 degrees; or j) said form is a propylene glycolsolvate of olanzapine and said PXRD pattern comprises peaks at 17.95 and20.65 degrees; or k) said form is a propylene glycol solvate ofolanzapine and said PXRD pattern comprises a peak at 8.33 degrees. 3.The composition according to claim 2, wherein: a) said form is apropylene glycol solvate of olanzapine and said PXRD pattern comprisespeaks at 8.33, 15.61, and 21.41 degrees; or b) said form is a propyleneglycol solvate of olanzapine and said PXRD pattern comprises peaks at8.33, 8.95, 14.47, 15.61, 17.95, and 23.29 degrees; or c) said form is apropylene glycol solvate of olanzapine and said PXRD pattern comprisespeaks at 8.33 and 21.41 degrees.
 4. The composition according to claim2, wherein said form is a propylene glycol solvate of olanzapine andsaid PXRD pattern comprises a peak at 8.33 degrees.
 5. The compositionaccording to claim 2, wherein: a) said form is a propylene glycolsolvate of olanzapine and said PXRD pattern comprises peaks at 8.95,14.47, 22.03, and 23.29 degrees; or b) said form is a propylene glycolsolvate of olanzapine and said PXRD pattern comprises peaks at 14.47,17.95, 19.57, and 20.65 degrees; or c) said form is a propylene glycolsolvate of olanzapine and said PXRD pattern comprises peaks at 14.47,15.61, and 20.65 degrees; or d) said form is a propylene glycol solvateof olanzapine and said PXRD pattern comprises peaks at 14.47 and 22.03degrees.
 6. The composition according to claim 2, wherein said form is apropylene glycol solvate of olanzapine and said PXRD pattern comprises apeak at 14.47 degrees.
 7. The composition according to claim 2, whereinsaid form is a propylene glycol solvate of olanzapine and said PXRDpattern comprises peaks at 17.95 and 20.65 degrees.
 8. The compositionaccording to claim 1, wherein the API is cortisone acetate and thecomposition is characterized by a PXRD pattern comprising peaksexpressed in terms of 2-theta angles, wherein: a) said form is apropylene glycol solvate of cortisone acetate and said PXRD patterncomprises peaks at 10.71, 14.54, and 18.49 degrees; or b) said form is apropylene glycol solvate of cortisone acetate and said PXRD patterncomprises peaks at 5.31, 15.66, 21.33, and 23.49 degrees; or c) saidform is a propylene glycol solvate of cortisone acetate and said PXRDpattern comprises peaks at 5.31, 10.71, 14.54, 15.66, 18.49, 21.33, and23.49 degrees; or d) said form is a propylene glycol solvate ofcortisone acetate and said PXRD pattern comprises peaks at 14.54 and18.49 degrees; or e) said form is a propylene glycol solvate ofcortisone acetate and said PXRD pattern comprises peaks at 15.66 and21.33 degrees; or f) said form is a propylene glycol solvate ofcortisone acetate and said PXRD pattern comprises a peak at 5.31degrees; or g) said form is a propylene glycol solvate of cortisoneacetate and said PXRD pattern comprises a peak at 18.49.
 9. Thecomposition according to claim 8, wherein said form is a propyleneglycol solvate of cortisone acetate and said PXRD pattern comprises apeak at 18.49.
 10. The composition according to claim 8, wherein saidform is a propylene glycol solvate of cortisone acetate and said PXRDpattern comprises a peak at 5.31 degrees.
 11. The composition accordingto claim 8, wherein: a) said form is a propylene glycol solvate ofcortisone acetate and said PXRD pattern comprises peaks at 10.71, 14.54,and 18.49 degrees; or b) said form is a propylene glycol solvate ofcortisone acetate and said PXRD pattern comprises peaks at 14.54 and18.49 degrees.
 12. The composition according to claim 8, wherein saidform is a propylene glycol solvate of cortisone acetate and said PXRDpattern comprises peaks at 15.66 and 21.33 degrees.
 13. The compositionaccording to claim 8, wherein: a) said form is a propylene glycolsolvate of cortisone acetate and said PXRD pattern comprises peaks at5.31, 15.66, 21.33, and 23.49 degrees; or b) said form is a propyleneglycol solvate of cortisone acetate and said PXRD pattern comprisespeaks at 5.31, 10.71, 14.54, 15.66, 18.49, 21.33, and 23.49 degrees. 14.The composition according to claim 1, wherein the API is a sodium saltof naproxen and the composition is characterized by a PXRD patterncomprising peaks expressed in terms of 2-theta angles, wherein: a) saidform is a propylene glycol solvate of a sodium salt of naproxen and saidPXRD pattern comprises peaks at 6.67, 18.55, and 22.79 degrees; b) saidform is a propylene glycol solvate of a sodium salt of naproxen and saidPXRD pattern comprises peaks at 9.65, 15.77, and 20.83 degrees; c) saidform is a propylene glycol solvate of a sodium salt of naproxen and saidPXRD pattern comprises peaks at 6.67 and 18.55 degrees; d) said form isa propylene glycol solvate of a sodium salt of naproxen and said PXRDpattern comprises a peak at 9.65 degrees; f) said form is a propyleneglycol solvate of a sodium salt of naproxen and said PXRD patterncomprises a peak at 6.67 degrees; g) said form is a propylene glycolsolvate of a sodium salt of naproxen and said PXRD pattern comprisespeaks at 15.77, 18.55, and 27.17 degrees; or h) said form is a propyleneglycol solvate of a sodium salt of naproxen and said PXRD patterncomprises peaks at 9.65 and 22.79 degrees.
 15. The composition accordingto claim 14, wherein said form is a propylene glycol solvate of a sodiumsalt of naproxen and said PXRD pattern comprises a peak at 9.65 degrees.16. The composition according to claim 14, wherein said form is apropylene glycol solvate of a sodium salt of naproxen and said PXRDpattern comprises a peak at 6.67 degrees.
 17. The composition accordingto claim 14, wherein: a) said form is a propylene glycol solvate of asodium salt of naproxen and said PXRD pattern comprises peaks at 6.67,18.55, and 22.79 degrees; or b) said form is a propylene glycol solvateof a sodium salt of naproxen and said PXRD pattern comprises peaks at6.67 and 18.55 degrees.
 18. The composition according to claim 14,wherein said form is a propylene glycol solvate of a sodium salt ofnaproxen and said PXRD pattern comprises peaks at 15.77, 18.55, and27.17 degrees; or


19. The composition according to claim 14, wherein: a) said form is apropylene glycol solvate of a sodium salt of naproxen and said PXRDpattern comprises peaks at 9.65 and 22.79 degrees; or b) said form is apropylene glycol solvate of a sodium salt of naproxen and said PXRDpattern comprises peaks at 9.65, 15.77, and 20.83 degrees.
 20. Thecomposition according to claim 1, wherein said form is a propyleneglycol solvate of celecoxib sodium trihydrate and the composition ischaracterized by a PXRD pattern comprising peaks expressed in terms of2-theta angles, said PXRD pattern comprising: a) any 1, 2, 3, 4, 5, 6,7, 8, 9, 10 or more peaks selected from peaks at 3.47, 6.97, 10.37,13.97, 16.41, 19.45, 21.29, 22.69, 23.87 or 25.75 degrees; or b) any 1,2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or more peaks at 3.43, 6.95, 10.25,13.95, 16.39, 17.39, 17.75, 18.21, 19.43, 21.21, 22.61 or 25.71 degrees.21. The composition according to claim 1, wherein said form is apropylene glycol solvate of a sodium salt of celecoxib and thecomposition is characterized by a PXRD pattern comprising peaksexpressed in terms of 2-theta angles, said PXRD pattern comprising: any1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 of the following peaks: 3.77, 7.57,8.21, 11.33, 14.23, 16.13, 18.69, 20.65, 22.69 and 24.77 degrees
 22. Thecomposition according to claim 1, wherein said form is a propyleneglycol solvate of a sodium salt of celecoxib and said composition ischaracterized by a PXRD pattern that comprises a peak at 8.21 degrees2-theta.
 23. The composition according to claim 1, wherein said form isa propylene glycol solvate of a sodium salt of celecoxib and saidcomposition is characterized by a PXRD pattern that comprises a peak at8.79 degrees 2-theta.
 24. The composition according to claim 1, whereinsaid form is a propylene glycol solvate of a calcium salt of celecoxiband the composition is characterized by a PXRD pattern comprising peaksexpressed in terms of 2-theta angles, said PXRD pattern comprising any1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 of the following: 3.75, 7.47, 11.33,14.89, 15.65, 18.31, 20.49, 21.73, 22.51 or 24.97.
 25. The compositionaccording to claim 1, wherein said form is a propylene glycol solvate ofa lithium salt of celecoxib and the composition is characterized by aPXRD pattern comprising peaks expressed in terms of 2-theta angles, saidPXRD pattern comprising any 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 of3.79, 7.51, 8.19, 9.83, 11.41, 15.93, 18.29, 19.19, 19.87, 20.63, 22.01or 25.09.